Cajal-Retzius cells (CRs) are among the first generated neurons of the developing cortex and play critical roles by secreting the glycoprotein reelin, which is essential for the correct formation of cortical layers and hippocampal architecture. For a long time, CRs have been considered transient neurons, which completely disappear early after birth, presumably after having completed their development-related functions. However, in contrast to other cortical regions, several reports have indicated that CRs never completely disappear from the mature hippocampus of several species. This surprising difference remains currently unexplained. The overarching purpose of this grant is to test the hypothesis that the ?unique? permanence of CRs in the adult hippocampus is required by a ?unique? hippocampal property (compared to other cortical areas), which is the ability to sustain adult neurogenesis. We provide preliminary data that show quantitatively that CRs remain at substantial levels in the hippocampus of adult mice and that their densities are increased by in vivo treatments that enhance hippocampal neurogenesis such as environmentally-enriched housing conditions. Although very intriguing, this finding remains, nevertheless, correlative. The research plan of this application aims to design experiments that can provide initial evidence for a direct causal link and unravel previously undescribed network mechanisms that modulate hippocampal postnatal neurogenesis. Hippocampal adult neurogenesis has been proposed to underlie critical cognitive functions, to be involved in the therapeutic effects of antidepressants, and potentially play a role in the pathobiology of several neurological diseases and psychiatric illnesses. Therefore, advancing our mechanistic knowledge on the cellular/network mechanisms involved in neurogenesis regulation is highly significant from both basic science and translational perspectives.